Method and device for radiotherapy

ABSTRACT

A radiotherapy method, comprising positioning a predetermined amount of a radionuclide selected from the group consisting of Radium-223, Radium-224, Radon-219 and Radon-220, in proximity to and/or within a tumor of a subject, for a predetermined time period. The predetermined amount and the predetermined time period are selected sufficient for the radionuclide to administering a predetermined therapeutic dose of decay chain nuclei and alpha particles into the tumor.

RELATED APPLICATIONS

This application is a divisional filing of U.S. patent application Ser.No. 10/554,743, filed on Oct. 28, 2005, which is a US National Phase ofPCT Patent Application No. PCT/IL2004/000363, filed on Apr. 29, 2004,which claims the benefit under 35 U.S.C. §119(e) of U.S. ProvisionalPatent Application No. 60/466,408, filed on Apr. 30, 2003. The contentsof the above Applications are all incorporated herein by reference.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to radiotherapy and, more particularly, toa method and device for radiotherapy using decay chain nuclei of aradionuclide.

Cancer is a major cause of death in the modern world. Effectivetreatment of cancer is most readily accomplished following earlydetection of malignant tumors. Most techniques used to treat cancer(other than chemotherapy) are directed against a defined tumor site inan organ, such as brain, breast, ovary, colon and the like.

When a mass of abnormal cells is consolidated and is sufficiently large,surgical removal, destruction of the tumor mass using heating, cooling,irradiative or chemical ablation becomes possible because the target isreadily identifiable and localizable. However, it is not uncommon for acancer that has initially occurred at a primary site to metastasize andspread into adjacent organs as diffuse clusters of abnormal cells.

Known in the art are several procedures for treating tumors byirradiation. One such procedure employs laser light, which can destructunwanted cells either through a direct interaction between the laserbeam and the tissue, or through activation of some photochemicalreactions using light-activated molecules which are injected into orotherwise administered to the tissue. For example, in a procedure, knownas Photo-dynamic therapy (PDT), a photosensitive drug that binds torapidly dividing cells is administered to the subject. Subsequently, thephotosensitive drug is irradiated using a narrow-band laser so as toinduce a chemical reaction resulting in a production of reactiveproducts which then destroy the abnormal tissue.

The PDT technique suffers from a number of drawbacks and limitations. Itis necessary to deliver a large amount of light radiation to the tumorat specific wavelengths to activate the photosensitive agent. Mostphotosensitive agents are activated at wavelengths that can onlypenetrate through three or less centimeters of tissue. Hence, non- orminimal-invasive PDT can be used for cancerous growths that are on ornear the surface of the skin, or on the lining of internal organs.

Radiation therapy, also referred to as radiotherapy, or therapeuticradiology, is the use of radiation sources in the treatment or relief ofdiseases. Radiotherapy typically makes use of ionizing radiation, deeptissue-penetrating rays, which can physically and chemically react withdiseased cells to destroy them. Each therapy program has a radiationdosage defined by the type and amount of radiation for each treatmentsession, frequency of treatment session and total of number of sessions.

Radiotherapy is particularly suitable for treating solid tumors, whichhave a well-defined spatial contour. Such tumors are encountered inbreast, kidney and prostate cancer, as well as in secondary growths inthe brain, lungs and liver.

Conventionally, the mainstream of the radiotherapy is toward theso-called treatment through external irradiation, that is, treating aninternal tumor grown in a human subject with a radiation of an externalsource (e.g., of gamma rays). Alternatively, a radioactive source(typically an electron emitting source) is inserted into the body.

To avoid adversely affecting any healthy region of the subject, oneattempts to maximize the dose administered to the target zone (to ensurekilling the cancerous cells) while minimizing the dose to other regions(to avoid undesirable damage). Most commonly, radiotherapy is used as anadjunct way of use, such as treating those remnant, not entirelyremoved, tumor cells by being exposed to a radiation dose of an externalsource after the surgical opening of the human body, removal ofmalignant tumors and the suture of the body parts or radiating theradiation dose directly to the remnant tumor cells before the suture ofthe body parts involved.

It is well known that different types of radiation differ widely intheir cell killing efficiency. Gamma and beta rays have a relatively lowefficiency. By contrast, alpha particles as well as other heavy chargedparticles are capable of transferring larger amount of energies, hencebeing extremely efficient. In certain conditions, the energy transferredby a single heavy particle is sufficient to destroy a cell. Moreover,the non-specific irradiation of normal tissue around the target cell isgreatly reduced or absent because heavy particles can deliver theradiation over the distance of a few cells diameters.

On the other hand, the fact that their range in human tissue is lessthan 0.1 millimeter, limits the number of procedures in which heavyparticles can be used. More specifically, conventional radiotherapy byalpha particles is typically performed externally when the tumor is onthe surface of the skin.

There is thus a widely recognized need for, and it would be highlyadvantageous to have a method and device for radiotherapy using alphaparticles and decay chain nuclei of a radionuclide, devoid of the abovelimitations.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided aradiotherapy method, comprising positioning a predetermined amount of aradionuclide selected from the group consisting of Radium-223,Radium-224, Radon-219 and Radon-220, in proximity to and/or within atumor of a subject, for a predetermined time period, the predeterminedamount and the predetermined time period selected sufficient for theradionuclide to administer a predetermined therapeutic dose of decaychain nuclei and alpha particles into the tumor.

According to further features in preferred embodiments of the inventiondescribed below, the method further comprises removing the radionuclideof the tumor once the predetermined therapeutic dose of decay chainnuclei and alpha particles is administered.

According to another aspect of the present invention there is provided amethod of removing a tumor and remnants thereof present in a body of asubject, the method comprising: (a) debulking at least a portion of thetumor and exposing tissue surrounding the tumor; and (b) positioning apredetermined amount of a radionuclide selected from the groupconsisting of Radium-223, Radium-224, Radon-219 and Radon-220, inproximity to and/or within the surrounding tissue, for a predeterminedtime period, the predetermined amount and the predetermined time periodselected sufficient for the radionuclide to administer a predeterminedtherapeutic dose of decay chain nuclei and alpha particles into thesurrounding tissue.

According to further features in preferred embodiments of the inventiondescribed below, the debulking is performed laparoscopically.

According to still further features in the described preferredembodiments the debulking is performed endoscopically.

According to still further features in the described preferredembodiments the debulking is performed surgically.

According to still further features in the described preferredembodiments the debulking is performed ablatively.

According to still further features in the described preferredembodiments the debulking is by a laser beam.

According to still further features in the described preferredembodiments the debulking comprises applying heat to the tumor.

According to still further features in the described preferredembodiments the debulking is by a microwave antenna.

According to still further features in the described preferredembodiments the debulking is by a radiofrequency electrode.

According to still further features in the described preferredembodiments the debulking is by an ultrasound device.

According to still further features in the described preferredembodiments the positioning of the radionuclide is by at least oneradiotherapy device having a surface whereby the radionuclide is on orbeneath the surface.

According to still further features in the described preferredembodiments the radiotherapy device comprises a needle.

According to still further features in the described preferredembodiments the radiotherapy device comprises at least one bead.

According to still further features in the described preferredembodiments the radionuclide is soluble in a solute and further whereinthe positioning the radionuclide comprises administering to the subjectin proximity to and/or within the tumor a solution of the radionuclidein the solute.

According to still further features in the described preferredembodiments the method further comprising recording a dose of the alphaparticles.

According to still further features in the described preferredembodiments the recording is by a sheet of photoluminescent material.

According to still further features in the described preferredembodiments the recording is by a sheet of photostimulable phosphor.

According to still further features in the described preferredembodiments the predetermined time is from about 10 seconds to about 10hours.

According to still further features in the described preferredembodiments the predetermined time is a few days.

According to an additional aspect of the present invention there isprovided a radiotherapy device, comprising a probe adapted for being atleast partially introduced into a body of a subject, and a radionuclideselected from the group consisting of Radium-223 and Radium-224, theradionuclide being on or beneath a surface of the probe, in a mannersuch that decay chain nuclei and alpha particles of the radionuclide areemitted outside the surface.

According to further features in preferred embodiments of the inventiondescribed below, the probe is coated by a protective coat.

According to still further features in the described preferredembodiments at least one of a thickness and a material of the protectivecoat is selected so as not to prevent the emission of the decay chainnuclei and the alpha particles.

According to still further features in the described preferredembodiments the probe comprises an inner elongated member and an outertubular member having a mouth section configured for receiving the innerelongated member, the inner elongated member being movable within theouter tubular member and having a distal end and a proximal end, wherebythe radionuclide is on or beneath a surface of the distal end.

According to still further features in the described preferredembodiments the device further comprising an operating wire, connectedto the proximal end of the inner elongated member.

According to still further features in the described preferredembodiments the device further comprising a detector, capable ofdetecting the radionuclide, the decay chain nuclei and the alphaparticles.

According to still further features in the described preferredembodiments the detector is operatively associated with the probe.

According to still further features in the described preferredembodiments the detector is adapted for being inserted through the mouthsection.

According to still further features in the described preferredembodiments the detector comprises a photoluminescent material.

According to still further features in the described preferredembodiments the detector comprises a photostimulable phosphor.

According to still further features in the described preferredembodiments the probe is capable of releasing at least a portion of theradionuclide therefrom, thereby allowing distribution of theradionuclide prior to the emission of the decay chain nuclei and alphaparticles.

According to still further features in the described preferredembodiments the release of the at least a portion of the radionuclide isby body fluids.

According to yet another aspect of the present invention there isprovided a method of manufacturing a radiotherapy device, the methodcomprising: (a) providing a probe having a surface; (b) positioning thesurface in a flux of a radionuclide; and (c) collecting nuclei of theradionuclide on or beneath the surface; thereby manufacturing theradiotherapy device.

According to further features in preferred embodiments of the inventiondescribed below, the collecting is by direct implantation in a vacuum.

According to still further features in the described preferredembodiments the collecting is by connecting the surface to a voltagesource of negative polarity.

According to still further features in the described preferredembodiments the positioning of the surface in the flux of theradionuclide is in a gaseous environment.

According to still further features in the described preferredembodiments a pressure of the gaseous environment and a voltage of thevoltage source are selected such that a velocity of nuclei is reduced toa thermal velocity.

According to still further features in the described preferredembodiments the steps (b) and (c) are done in a manner such that decaychain nuclei and alpha particles of the radionuclide are emitted outsidethe surface.

According to still further features in the described preferredembodiments the probe comprises at least one needle.

According to still further features in the described preferredembodiments the probe comprises at least one bead.

According to still further features in the described preferredembodiments the probe is a tip of an endoscope.

According to still further features in the described preferredembodiments the probe is a tip of a laparoscope.

According to still further features in the described preferredembodiments the probe is a tip of an imaging device.

According to still further features in the described preferredembodiments the probe comprises an inner elongated member and an outertubular member having a mouth section configured for receiving the innerelongated member, the inner elongated member being movable within theouter tubular member and having a distal end and a proximal end, wherebythe radionuclide is collected on or beneath a surface of the distal end.

According to still further features in the described preferredembodiments the outer tubular member comprises at least one window, forallowing protrusion of the distal end of the inner elongated membertherethrough.

According to still further features in the described preferredembodiments at least one window is on a side wall of the outer tubularmember.

According to still further features in the described preferredembodiments the outer tubular member is made of a material capable ofabsorbing the decay chain nuclei and the alpha particles.

According to still further features in the described preferredembodiments the inner elongated member and the outer tubular member areeach independently flexible.

According to still further features in the described preferredembodiments the method further comprising coating the surface by aprotective coat.

According to still further features in the described preferredembodiments at least one of a thickness and a material of the protectivecoat is selected so as not to prevent emission of decay chain nuclei andalpha particles from the surface of the probe.

According to still further features in the described preferredembodiments an outgoing flux of the decay chain nuclei is from about 10²to about 10⁵ atoms/sec.

According to still further features in the described preferredembodiments a surface density of the radionuclide is from about 10¹⁰ toabout 10¹³ atoms/cm².

According to still further features in the described preferredembodiments the probe is capable of administering from about 100 rem toabout 100000 rem of radiation.

According to still further features in the described preferredembodiments the probe is capable of administering from about 1000 toabout 10000 rem of radiation.

According to still further features in the described preferredembodiments an activity of the radionuclide is from about 10 nanoCurieto about 10 microCurie.

According to still further features in the described preferredembodiments an activity of the radionuclide is from about 10 nanoCurieto about 1 microCurie.

According to still another aspect of the present invention there isprovided a method of preparing a radioactive surface source, the methodcomprising: (a) providing a solution containing a predetermined amountof a radioactive isotope; and (b) spreading the solution on a metalsurface so as to provide an admixture of the metal and the solution;thereby providing the radioactive surface source.

According to further features in preferred embodiments of the inventiondescribed below, the solution is acidic solution.

According to still further features in the described preferredembodiments the radioactive isotope comprises Uranium-232.

According to still further features in the described preferredembodiments the radioactive isotope comprises uranyl chloride.

According to still further features in the described preferredembodiments the acidic solution comprises hydrochloric acid.

According to still further features in the described preferredembodiments the metal surface is prepared by evaporating at least onemetal on a substrate.

According to still further features in the described preferredembodiments the metal surface comprises at least one metal selected fromthe group consisting of nickel, molybdenum and palladium.

According to still further features in the described preferredembodiments the substrate is made of silicon.

According to still further features in the described preferredembodiments the method further comprising cooling the metal prior to thespreading the layer of the acidic solution thereon.

According to still further features in the described preferredembodiments the method further comprising applying a flow of gas on themetal, substantially contemporaneously with the spreading the layer ofthe acidic solution.

According to still further features in the described preferredembodiments the gas is air.

The present invention successfully addresses the shortcomings of thepresently known configurations by providing a method, and device capableof performing radiotherapy using alpha radiation.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. In case of conflict, the patentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Implementation of the method and system of the present inventioninvolves performing or completing selected tasks or steps manually,automatically, or a combination thereof. Moreover, according to actualinstrumentation and equipment of preferred embodiments of the method andsystem of the present invention, several selected steps could beimplemented by hardware or by software on any operating system of anyfirmware or a combination thereof. For example, as hardware, selectedsteps of the invention could be implemented as a chip or a circuit. Assoftware, selected steps of the invention could be implemented as aplurality of software instructions being executed by a computer usingany suitable operating system. In any case, selected steps of the methodand system of the invention could be described as being performed by adata processor, such as a computing platform for executing a pluralityof instructions.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only, and are presentedin the cause of providing what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the invention. In this regard, no attempt is made to show structuraldetails of the invention in more detail than is necessary for afundamental understanding of the invention, the description taken withthe drawings making apparent to those skilled in the art how the severalforms of the invention may be embodied in practice.

In the drawings:

FIG. 1 a is a schematic illustration of a radiotherapy device, accordingto a preferred embodiment of the present invention;

FIG. 1 b is a schematic illustration of the radiotherapy device, in apreferred embodiment in which beads are employed;

FIG. 1 c is a schematic illustration of the radiotherapy device, in apreferred embodiment in which, the device comprises an inner elongatedmember and an outer tubular member;

FIG. 1 d is a schematic illustration of the radiotherapy device of FIG.1 c, in a preferred embodiment in which the inner elongated memberprotrudes through a window formed in a wall of the outer tubular member;

FIGS. 2 a-c show experimental setup of an experiment in which aradionuclide was embedded on a needle, using electrostatic forces,according to a preferred embodiment of the present invention;

FIGS. 3 a-b show activity distribution of a collector (FIG. 3 a) and asource (FIG. 3 b) in an experiment in which a surface source of U-232was prepared, according to a preferred embodiment of the presentinvention;

FIGS. 4 a-d are schematic illustrations of detecting probes used in anin vivo experiment on mice having a LAPC4 prostate tumor, according to apreferred embodiment of the present invention;

FIG. 5 is a schematic illustration of slices made on a tumor in an exvivo experiment on mice having a LAPC4 prostate tumor, according to apreferred embodiment of the present invention;

FIG. 6 a is an image recorded by the detecting probe of FIG. 4 a;

FIG. 6 b is a radiation graph corresponding to the image of FIG. 6 a;

FIG. 7 a is an image recorded by the detecting probe of FIG. 4 b;

FIG. 7 b is a radiation graph corresponding to the image of FIG. 7 a;

FIG. 8 a is an image recorded by the detecting probe of FIG. 4 c;

FIG. 8 b is a radiation graph corresponding to the image of FIG. 8 a;

FIG. 9 is an image of radiation patterns of the slices of FIG. 5; and

FIGS. 10 a-f are images (FIGS. 10 a, 10 c and 10 e) and correspondingradiation graphs (FIGS. 10 b, 10 d and 10 f, respectively) of threeconsecutive radiation measurements in an experiment on mice having aB-16 Melanoma.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of a method and device which can be used inradiotherapy. Specifically, the present invention can be used to locallydestroy tumors in either invasive or non-invasive procedures utilizingdecay chain nuclei of a radionuclide, such as, but not limited to,Radium-223, Radium-224, Radon-219 and Radon-220.

The principles and operation of a method and device for radiotherapyaccording to the present invention may be better understood withreference to the drawings and accompanying descriptions.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and the arrangement of the components setforth in the following description or illustrated in the drawings. Theinvention is capable of other embodiments or of being practiced orcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein is for the purpose ofdescription and should not be regarded as limiting.

Radiation is a flow of subatomic or atomic particles or waves, which canbe emitted by nuclei of a radioactive substance when the nuclei undergodecay processes. One typically encounters four types of radiation: (i)alpha radiation, in a form of helium nuclei, also referred to as alphaparticles; (ii) beta radiation, in a form of electrons or positrons,(iii) gamma radiation, in a form of electromagnetic waves or photons;and (iv) neutron radiation, in a form of neutral nucleons.

The rate at which nuclei of a radioactive substance undergo decay andemit radiation is directly proportional to the number of radioactivenuclei in the substance that can decay. Hence, as time goes on, thenumber of radioactive nuclei in the substance is reduced, and the decayrate decreases. The period of time over which the number of radioactivenuclei of a radioactive substance decreases by a factor of one-half, isreferred to as the half-life of the substance. In general, radioactivedecay is a quantum mechanical process governed by wavefunctions thesquare of which is interpreted as probability. In a short period oftime, each radioactive nucleus has a certain probability of decaying,but whether it actually does is determined by random chance. When aradioactive nucleus has more than one decay channels, the probability ofdecaying in a certain channel is referred to as the branching ratio ofthe channel.

Nuclei which emit alpha particles, also known as alpha emitters, aretypically heavy nuclei in which the ratio of neutrons to protons is toolow. Following emission of an alpha particle (two protons and twoneutrons) from such a nucleus, the ratio is increased and the nucleusbecomes more stable. Since the number of protons in the nucleus of anatom determines the element, the loss of an alpha particle actuallychanges the atom to a different element. For example, Polonium-210 (Po)has 126 neutrons and 84 protons, corresponding to a ratio of 3:2. Whenan atom of Po-210 emits an alpha particle, the ratio is increased byabout 1%, resulting in a stable Lead-206 (Pb) atom, having 124 neutronsand 82 protons.

Of the aforementioned four types of radiations, alpha particles are theheaviest, about 7000 times the electron's mass, and have the shortestrange in human tissue, less than 0.1 millimeter. Conventionalradiotherapy procedures by alpha particles are therefore effective onlyfor tumors on or close beneath the surface of the skin.

While conceiving the present invention it has been hypothesized andwhile reducing the present invention to practice it has been realizedthat radiotherapy by alpha radiation can be employed also for tumorsdeep inside the body.

Hence, according to one aspect of the present invention there isprovided a radiotherapy method, in which a predetermined amount of aradionuclide is positioned in proximity to and/or within a tumor of asubject, for a predetermined time period.

As used herein “in proximity to a tumor” refers to a sufficient distancefor allowing alpha particles or decay chain nuclei of the radionuclideto arrive at the tumor. Preferably, the distance between theradionuclide and the tumor is below 0.1 mm, more preferably below 0.05mm, most preferably below 0.001 mm.

According to a preferred embodiment of the present invention, thepredetermined amount of radionuclide and the predetermined time periodare preferably selected sufficient for the radionuclide to administer apredetermined therapeutic dose of decay chain nuclei and alpha particlesinto the tumor.

The radionuclide is preferably a relatively short lived radio-isotope,such as, but not limited to, Radium-223, Radium-224, Radon-219,Radon-220 and the like. When Radium 223 is employed, the following decaychain is emitted therefrom:

Ra-223 decays, with a half-life period of 11.4 d, to Rn-219 by alphaemission;

Rn-219 decays, with a half-life period of 4 s, to Po-215 by alphaemission;

Po-215 decays, with a half-life period of 1.8 ms, to Pb-211 by alphaemission;

Pb-211 decays, with a half-life period of 36 m, to Bi-211 by betaemission;

Bi-211 decays, with a half-life period of 2.1 m, to Tl-207 by alphaemission; and

Tl-207 decays, with a half-life period of 4.8 m, to stable Pb-207 bybeta emission.

As can be understood from the above decay chain, when Rn-219 is employedas the radionuclide, the decay chain begins with the decay of Rn-219 toPo-215, and continues to Pb-211, Bi-211, Tl-207 and Pb-207.

When Radium 224 is employed, the following decay chain is emittedtherefrom:

Ra-224 decays, with a half-life period of 3.7 d, to Rn-220 by alphaemission;

Rn-220 decays, with a half-life period of 56 s, to Po-216 by alphaemission;

Po-216 decays, with a half-life period of 0.15 s, to Pb-212 by alphaemission;

Pb-212 decays, with a half-life period of 10.6 h, to Bi-212 by betaemission;

Bi-212 decays, with a half-life of 1 h, to Tl-208 by alpha emission (36%branching ratio), or to Po-212 by beta emission (64% branching ratio);

Tl-208 decays, with a half-life of 3 m, to stable Pb-208 by betaemission; and

Po-212 decays, with a half-life of 0.3 μs, to stable Pb-208 by alphaemission.

As can be understood from the above decay chain, when Rn-220 is employedas the radionuclide, the decay chain begins with the decay of Rn-220 toPo-216, and continues to Pb-212, Bi-212, Tl-208 (or Po-212) and Pb-208.

In any event when the radionuclide is positioned in proximity to and/orwithin a tumor, a plurality of short-lived atoms are released into thesurrounding environment and dispersed therein by thermal diffusionand/or by convection via body fluids. The short-lived atoms and theirmassive decay products (i.e., alpha particles and daughters nuclei),either interact with the cells of the tumor or continue the decay chainby producing smaller mass particles. As will be appreciated by oneordinarily skilled in the art, the close proximity between theradionuclide and the tumor, and the large number of particles which areproduced in each chain, significantly increase the probability ofdamaging the cells of interest, hence allowing for an efficienttreatment of the tumor.

The method of the present invention can be employed either as a standalone procedure or as a supplementary method to conventional debulkingprocedures for surgically removing or ablating a tumor. In typicalconventional debulking procedures, once the tumor is removed, remnantsof the tumor may be still present in tissue surrounding the region whichwas surgically removed or ablated. Hence, according to a preferredembodiment of the present invention the radionuclide can be positionedin proximity or within the surrounding tissue, again, for apredetermined time period, so as to administer the decay chain nucleiand alpha particles into the surrounding tissue.

This embodiment can be employed subsequently or contemporaneously to anydebulking procedure known in the art, including, without limitation afull invasive procedure, a laparoscopic procedure and an endoscopicprocedure. Many methods of debulking tumors are contemplated. Forexample, in one embodiment the debulking procedure is performedsurgically, e.g., by dissecting the tumor or the surrounding tissueusing a conventional scalpel or any other mechanical device; in anotherembodiment the debulking procedure is performed ablatively, e.g., byheating or irradiating the tumor, for example, by laser or ultrasonicradiation. The above and other procedures may include the use of a laserdevice, microwave antenna, a radiofrequency electrode, an ultrasounddevice and the like.

According to a preferred embodiment of the present invention, theradionuclide can be inserted into the body of the subject and positionedin proximity to and/or within the tumor by more than one way.

Hence, in one embodiment, the radionuclide is soluble in a solute andthe positioning of the radionuclide is by administering a solution ofthe radionuclide in the solute to the subject in proximity to and/orwithin the tumor. In another embodiment, the positioning of theradionuclide is by at least one radiotherapy device, whereby theradionuclide is on or beneath a surface of the device. A method ofpreparing a surface having the radionuclide is provided hereinafter andamplified in the Examples section that follows.

Referring now to the drawings, FIGS. 1 a-d illustrate a radiotherapydevice 10, in accordance with preferred embodiments of the invention. Inthe embodiment shown in FIG. 1 a, device 10 is preferably a probe 12whereby radionuclide 16 is on or beneath a surface 14 of probe 12. Probe12 can be, for example, a needle, or any other device adapted for beingat least partially introduced into a body of a subject. Representativeexamples include, without limitation, a tip of an endoscope, a tip of alaparoscope and a tip of an imaging device.

Referring to FIG. 1 b, in another embodiment, device 10 comprises one ormore beads 18 whereby radionuclide 16 is on or beneath a surface 20 ofbeads 18. Beads 18 can be distributed near or in the tumor, for exampleby injection or during an invasive procedure.

Referring to FIGS. 1 c-d, in an additional embodiment, device 10comprises an inner elongated member 22 and an outer tubular member 24,each independently can be rigid or flexible. Tubular member 24 ispreferably manufactured with a mouth section 26 configured for receivinginner member 22. Inner member 22 is preferably capable of moving, eitherlongitudinally or rotationally within tubular member 24. Radionuclide 16is on or beneath a surface 28 of a distal end 32 of inner member 22.When inner member 22 protrudes out of a window 34 of tubular member 24,many locations within the body of the subjects can be reached so as tobring radionuclide 16 into close proximity to the tumor. As shown inFIG. 1 d, window 34 can be formed in a side wall 36 of tubular member24, so as to facilitate rotational motion of device 10 and to allowinner member 22 to reach different portions of the body.

According to a preferred embodiment of the present invention device 10can also comprise an operating wire 38, connected to a proximal end 40of inner member 22. Wire 38 serves for operating device 10 through thebody of the subject. More specifically, wire 38 can be used by theoperator for providing inner member 22 with its longitudinal and/orrotational motion.

Tubular 24 can be made of a material which absorbs the decay chainnuclei and alpha particles of radionuclide 16, so that when distal end32 of inner member 22 does not protrude through window 34 radiation isat least partially blocked. This embodiment is particularly useful whenit is desired to temporarily cease the emission of radiation from device10 to the body of the subject, for example when during the delivery ofdevice 10 to the tumor, or to prevent interference with a certainmeasurement which may be performed simultaneously with the radiotherapyprocedure.

The advantage of using device 10 for positioning radionuclide 16 is thatwhen radionuclide 16 is confined to device 10, convection of radioactivematerial away from the tumor is substantially prevented. One of ordinaryskill in the art will appreciate that although a small portion of thedecay chain nuclei, emitted by radionuclide 16 can, in principle, betransported to healthy regions by body fluids, the effect of thisportion on the healthy tissue is minimized. Being spread in largevolume, the transported portion is extremely ineffective due to verysmall energy/mass ratio. Thus, with reference to the above decay chains,when device 10 comprises, for example, Ra-224, the Ra-224 atomspreferably remain in device 10 while the other decay chain nuclei andalpha particles are emitted therefrom. As the main radiation source isthe Ra-224, the confinement of Ra-224 to device 10 allows irradiating apredetermined volume of tissue surrounding device 10, whilesubstantially preventing damage to regions beyond the predeterminedvolume.

It is to be understood, that it is not intended to limit the scope ofthe present invention solely to radionuclide which is confined to device10. In some embodiments of the present invention, once radionuclide 16is delivered to a predetermined position it can be released from device10, for example, by allowing body fluids to wash radionuclide 16 offdevice 10.

According to a preferred embodiment of the present invention device 10can comprise a detector 42, for detecting alpha particles, radionuclide16 or its decay chain nuclei. This embodiment is particularly usefulwhen it is desired to monitor or record the amount of radiation whichwas delivered to the respective portion of the body of to the subject.Detector 42 can be connected to tubular member 24 or inner member 22, inwhich case detector 42 is preferably adapted for being inserted throughmouth section 26. Alternatively, detector 42 can be detached fromtubular member 24 or inner member 22, so as to allow separate insertionof detector 42 into the body. Detector 42 can be for example, a sheet ofa photoluminescent material, such as, but not limited to, a storagephosphor.

Storage phosphors, also known as photostimulable phosphors are commonlyused in radiography. Generally, storage phosphors retain a latent imagewhen exposed to a two dimensional pattern of radiation, analogous tofilm. The image is stored by exposing the molecules of thephotostimulable phosphors to the radiation thereby exciting them to along-lived isomeric state. After the exposure to the radiation, thelatent image can be read out by aiming a stimulating beam of light atdetector 42. The stimulating beam further excites the molecules to ahigher state from which they decay back by emitting a photon. Theemitted photons in turn can be converted into an electronic form by asuitable device, e.g., a photo multiplier tube (not shown) for furtherprocessing. As further demonstrated in the example section that follows,detector 42 is capable of detecting individual alpha particles.

As stated, the amount of radionuclide 16 which is inserted into the bodyof the subject and the time period during which radionuclide 16 emitsradiation, are preferably selected sufficient so as to administer apredetermined therapeutic dose of decay chain nuclei and alpha particlesinto the tumor. The radiation dose reflects the accumulated amount ofenergy deposited by the radiation in a unit mass. Typically, radiationdose is measured in units of rads, where one rad is equivalent to 100ergs/gr. In radiotherapy it is common to measure radiation doses inunits of rems, which reflect the damage incurred in the tissue due tothe radiation. For alpha particles, the one rad is equivalent to about20 rems.

The amount of radiation provided radionuclide 16 is preferably fromabout 100 rem to about 100000 rem, more preferably, from about 1000 toabout 10000 rem. In terms of particles flux, the outgoing flux of decaychain nuclei of radionuclide 16 is from about 10² to about 10⁵atoms/sec, more preferably from about 10³ to about 10⁴ atoms/sec.

As used herein the term “about” refers to ±10%.

According to a preferred embodiment of the present invention thedelivery of the aforementioned doses and fluxes can be done on more thanone time scale. Hence, in one embodiment, radionuclide 16 is insertedinto the body of the subject and allowed to completely decay in situ.

As used herein “a complete decay” of a radionuclide refers to anactivity reduction thereof by at least 98%.

The embodiment in which radionuclide 16 completely decays can beexecuted, for example, when device 10 comprises beads 18, or whenradionuclide 16 is soluble in a solution, as further detailedhereinabove. Alternatively, this embodiment can be executed bytemporarily implanting a tip of a needle (see, e.g., FIG. 1 a) withradionuclide 16 in proximity or near the tumor, and allowingradionuclide 16 to completely decay. Subsequently, the implantation canbe removed.

The advantage of allowing radionuclide 16 to completely decay, it thatin this embodiment the therapeutic dose of decay chain nuclei and alphaparticles is delivered over a relatively long period, during which thetime dependence of the radiation has a typical shape of a decayingexponent, characterized by a half-life of radionuclide 16. For example,if radionuclide 16 is Ra-224 the time dependence is characterized by ahalf-life of 3.7 days, and if radionuclide 16 is Ra-223, the timedependence is characterized by a half-life of 11.4 days.

According to a preferred embodiment of the present invention, whenradionuclide 16 is allowed to completely decay in situ, the total timeof treatment is from about 4 hours to about 70 days, for example, 4hours, 3 days, 20 days and the like.

In another embodiment, radionuclide 16 is positioned in proximity toand/or within a tumor of a subject, allowed to emit its decay chainnuclei and alpha particles, and, after a predetermined time period,removed from the body of the subject, preferably before a complete decayof radionuclide 16. This embodiment can be executed, for example, usingdevice 10 or any other medical instrument which can be inserted andextracted as desired. Suitable shapes of device 10 for this embodimentinclude, without limitations, a sufficiently long needle or any of theconfigurations shown in FIGS. 1 a, 1 c and 1 d. Additionally, device 10can comprise an endoscope tip, a laparoscope tip, an imaging device tipand the like, as further detailed hereinabove.

The advantage of this embodiment is that during the time period in whichradionuclide 16 is in the body, the device 10 can be repositioned,thereby making the treatment more selective in terms of the cells beingdestroyed. When device 10 is in place near or inside the tumor, theradiation rate is dominated by the decay rate of radionuclide 16, and istherefore substantially constant. Once extracted the decay chain nucleiwhich were emitted from device 10 remain in the body and continue todecay. The time dependence of the radiation one device 10 is extracted,has a typical shape of a decaying exponent, characterized by a half-lifeof the longest lived decay chain nucleus. For example, if radionuclide16 is Ra-224 the time dependence is characterized by the half-life ofPb-212 (10.6 hours), and if radionuclide 16 is Ra-223, the timedependence is characterized by the half-life of Pb-211 (36 minutes).

According to a preferred embodiment of the present invention, whenradionuclide 16 is temporarily inserted into the body, the total time oftreatment is from 10 seconds to a few hours, for example, 1 minute, 10minutes, 20 minutes and the like.

Whether radionuclide 16 is removed prior to its complete decay orallowed to completely decay in situ, its activity is selected so as toallow the administration of the aforementioned therapeutic dose into thetumor. The relation between the activity of radionuclide 16 and theadministered dose may depend on many factors such as, but not limitedto, the type and size of the tumor, the number of locations to whichradionuclide 16 is inserted (for example, when more than oneradiotherapy device is used), the distance between radionuclide 16 andthe tumor and the like. A typical activity of radionuclide 16 is,without limitation, from about 10 nanoCurie to about 10 microCurie, morepreferably from about 10 nanoCurie to about 1 microCurie.

The method and device of the present invention can be used to destroymany tumors. Typical tumors include, but are not limited to, breasttumor, brain tumor, neuroblastoma, thyroid gland tumor, gestationaltrophoblastic tumor, uterine sarcoma, carcinoid tumor, colon carcinoma,esophageal carcinoma, hepatocellular carcinoma, liver carcinoma,lymphoma, plasma cell neoplasm, mesothelioma, thymoma, alveolarsoft-part sarcoma, angiosarcoma, epithelioid sarcoma, extraskeletalchondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignantfibrous histiocytoma, malignant hemangiopericytoma, malignantmesenchymoma, malignant schwannoma, synovial sarcoma, melanoma,neuroepithelioma, osteosarcoma, leiomyosarcoma, Ewing sarcoma,osteosarcoma, rhabdomyo-sarcoma, hemangiocytoma, myxosarcoma,mesothelioma (e.g., lung mesothelioma), granulosa cell tumor, thecomacell tumor and Sertoli-Leydig tumor.

Hence, the method and device of the present invention can be used totreat many types of cancers, such as, but not limited to, vaginalcancer, vulvar cancer, cervical cancer, endometrial cancer, ovariancancer, rectal cancer, salivary gland cancer, laryngeal cancer,nasopharyngeal cancer, many lung metastases and acute or chronicleukemia (e.g., lymphocytic, Myeloid, hairy cell).

According to an additional aspect of the present invention there isprovided a method of manufacturing a radiotherapy device, e.g., device10. The method comprises the following method steps in which in a firststep, a probe having a surface is provided, in a second step, thesurface is positioned in a flux of a radionuclide, e.g., radionuclide16, and in a third step, nuclei of the radionuclide are collected on orbeneath the surface.

According to a preferred embodiment of the present invention thecollection of the radionuclide on the probe is done in a manner suchthat the natural recoil energy of the daughter nucleus of theradionuclide (typically of the order of 100 keV), is sufficiently largeso as to allow the daughter nucleus to escape the surface of the probe.This can be done by embedding the radionuclide on or beneath the surfaceof the probe, typically at a depth of the order of about 10 nanometers.Optionally and preferably, the outer layer of the probe can be made of aporous material so as to increase the probability of the escape.

As stated, radionuclide 16 is preferably a relatively short livedradio-isotope (e.g., Ra-224 or Ra-223), with a half-life of a few days.Thus, according to a preferred embodiment of the present invention, thecollection of the radionuclide on the probe is done with a minimal delayprior to its application. This can be achieved, for example, through theutilization of a flux generating surface source. For example, when theradionuclide is Ra-224, a flux thereof can be generated by a surfacesource of Th-228. A surface source of Th-228 can be prepared, forexample, by collecting Th-228 atoms emitted from a parent surface sourceof U-232. Such parent surface source can be prepared, for example, byspreading a thin layer of acid containing U-232 on a metal. Arepresentative example of preparing a surface source of Th-228 fromU-232 is provided hereinafter in the Examples section that follows.

Alternatively, a surface source of Th-228 can be obtained by collectinga beam of Fr-228 having a half-life of 39 seconds, which in turn decaysto Ra-228. The Ra-228 decays, with a half-life of 5.75 years, to Ac-228which in turn decays, with a half-life of 6 hours, by beta decay, toTh-228. The entire decay chain, Fr-228, Ra-228, Ac-228 and Th-228 is bybeta emission. The population of Th-228 is slowly built over a period ofthe order of a few years, approaching radioactive equilibrium withRa-228. Thus, the obtained Th-228 surface source is characterized by the5.75 years half-life of Ra-228 rather than by its own 1.9 yearshalf-life.

When the radionuclide is Ra-223, a flux thereof can be generated by asurface source of Ac-227, which is in radioactive equilibrium withTh-227. An Ac-227 surface source can be obtained by separating a beam ofFr-227 ions having an energy of a few tens of keV, and implanting theFr-227 ions in a foil at a depth of a few nanometers. Through a sequenceof two short half-life beta decays, the Fr-227 ions decay to Ac-227,thereby providing the desired Ac-227 surface source.

Available isotope separators for separating the Fr-227 or Fr-228include, without limitation, ISOLDE, located at CERN, Geneva or ISAC,located at TRIUMF, Vancouver.

The collection of the radionuclide on or beneath the surface of theprobe can be done in more than one way. For example, in one embodiment,the collection is by direct implantation in a vacuum. In thisembodiment, the surface source which generates the radionuclide flux isplaced in vacuum in close proximity to the probe. Nuclei recoiling fromthe surface source traverse the vacuum gap and being implanted in thesurface of the probe.

In an alternative embodiment, the collection is done by electrostaticforces. As the desorbing atoms from the surface source are positivelycharged (both due to the decay itself and as a result of passage throughlayers of the surface source material), an application of a suitablenegative voltage between the surface source and the probe, the desorbingnuclei of the radionuclide can be collected onto the outer surface ofthe probe. According to a preferred embodiment of the present invention,the collection is done under suitable gas pressure, so as to slow thevelocity of the nuclei to a thermal velocity, hence facilitating theircollection of the probe. According to a preferred embodiment of thepresent invention, the area of the probe is substantially smaller thanthe area of the surface source. Due to the electrostatic forces betweenthe probe and the desorbing atoms, substantially all the atoms desorbedfrom the surface source are captured on the surface of the probe. Oneordinarily skilled in the art would appreciate that as the area of theprobe is smaller than the area of the surface source, a highconcentration of the radionuclide on the probe can be achieved.Additionally the small size of the probe is advantageous especially inminimal invasive medical procedures. Preferably, the surface density ofthe radionuclide on the probe is from about 10¹⁰ to about 10¹³atoms/cm².

In still an alternative embodiment, the radionuclide can also becollected by separating a sufficiently energetic beam of theradionuclide (e.g., a beam of Ra-223 or a beam of Ra-224) and directingthe radionuclide beam onto the probe or positioning the probe in thepath of the radionuclide beam, so as to allow implanting theradionuclide in the surface of the probe. Radionuclide beams can beobtained, for example, using any of the aforementioned isotopeseparators.

Irrespective of the method used to collect the radionuclide on orbeneath the surface of the probe, the probe is preferably coated by aprotective coat, which may be, for example, a thin (e.g., a fewnanometers in thickness, say 5 nanometers) layer of Titanium. Theprotective coat serves for minimizing loss of radionuclide from theprobe when the probe is in physical contact with the body. Theprotective coat is preferably selected so as not to prevent emission ofdecay chain nuclei and alpha particles from the surface of the probe.

It is expected that during the life of this patent many relevantradiotherapy devices will be developed and the scope of the termradiotherapy devices is intended to include all such new technologies apriori.

Additional objects, advantages and novel features of the presentinvention will become apparent to one ordinarily skilled in the art uponexamination of the following examples, which are not intended to belimiting. Additionally, each of the various embodiments and aspects ofthe present invention as delineated hereinabove and as claimed in theclaims section below finds experimental support in the followingexamples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate the invention in a non limiting fashion.

Example 1 Electrostatic Embedment of Radionuclide on a Needle

The following is a description of a typical experiment in which ²²⁴Raatoms were electrostatically collected on a needle.

A 0.45 mm diameter nickel-plated stainless steel needle was held at adistance of about 1 cm from a 1 microCurie surface source of Th-228. Thedesorption probability of Ra-224 from the Th-228 was about 10%. Prior toelectrostatic collection, the needle was cleaned in acetone in anultrasonic bath for 20 minutes.

The experimental setup is shown in FIGS. 2 a-c. FIG. 2 a shows theTh-228 surface source. FIG. 2 b is a top-view of the Th-228 sourcemounted inside an electrostatic collection chamber. FIG. 2 c shows theneedle mounted on a vertical electrode positioned in front of the Th-228source. The potential difference between the needle and the Th-228source was 1000 V, and the electrostatic collection chamber was filledwith air at atmospheric pressure.

The Th-228 decayed by alpha emission into ionized atoms of Ra-224 havingsufficient kinetic energy to be emitted into the air. Due to atomiccollisions between the Ra-224 atoms and the air molecules, the kineticenergy was rapidly decreased, resulting in drifting of the Ra-224 atomsalong the electric field lines in the direction of the tip of theneedle. Upon impinging the needle, the Ra-224 atoms absorbed electronsfrom the nickel and remained on the surface thereof. The duration of theexperiment was 10 days, resulting in an accumulated Ra-224 activity ofabout 40 nanoCurie.

The needle was subsequently coated with a layer of about 50 Å oftitanium by sputtering. Once coated, the alpha particles spectrum of theneedle was measured using a standard solid state detector. A desorptionprobability of about 15% was measured for ²²⁰Rn atoms recoiling from thecoated surface.

To verify the stability of the coated needle, a few cycles of 1 minuterinsing in deionized water followed by 1 minute wash in dry N₂ wereperformed. The activity seemed to stabilize on 60% of its initial valueunder a plurality of such cycles.

Example 2 Preparation of a U-232

In this example, a U-232 surface source was prepared from an acidicsolution containing minute amounts of a uranium salt. The U-232 surfacesource can be used, for example, for the purpose of preparing a surfacesource of Th-228, e.g., the Th-228 surface source used in Example 1.

The primary material is a 2M hydrochloric acid containing uranylchloride at an activity density of 1 microCurie per microliter. Theactive material itself had an activity of 0.5 curie per gram,corresponding to an active to stable material ratio of about 1:40. Themixing of uranyl chloride with pure 2M hydrochloric acid, provided lowerconcentrations of active material.

A layer of about 200 nanometers of high purity (99.999%) nickel wasevaporated on a 2.5×2.5 cm² polished wafer of silicon. It is to beunderstood that the use of the above materials is not to be consideredas limiting and that other materials or compositions can be used. Forexample, the nickel can be replaced by any other slightly soluble metal,such as, but not limited to, molybdenum and palladium. The silicon had athin layer of native oxide, of about 2 nanometers. Although the rate ofreaction between the acid and the nickel is typically small, the waferwas cooled to a temperature of a few degrees centigrade, so as tofurther decrease the reaction rate.

Once cooled, an aliquot of about 1 microliter of the acid was depositedon the nickel surface, and immediately spread, substantially evenly, onabout 80% of the wafer's surface area.

During the entire spreading action a flow of dry air was applied to thesurface to accelerate the process of acid removal and to minimizeinteraction between the acid and the nickel. The deposited liquid waseasily and substantially uniformly spread over the surface area,resulting in a thin layer of nickel chloride admixed with the uranylchloride. The thickness of the layer was sufficiently small to allow asizable fraction of nuclei resulting from alpha decay to recoil out ofthe surface. Note that the amount of solid material in the solution wasnegligible compared to the nickel chloride layer, even for the primarysolution in its undiluted form (corresponding to an average thickness ofless than 1 nanometer).

To test the desorption probability from the U-232 source, the followingseries of measurements was taken.

The source was placed in vacuum in close proximity to a collectorsurface while preventing physical contact therebetween. Recoils from thesource were collected by collector surface for about 50 hours and thealpha particle spectra of both source and collector were measured. Ahigh statistical accuracy of a few percents was established. Thedesorption probability was then determined from the measured alphaparticle spectra of parent nucleus (Th-228) on the source and ofdaughter nucleus (Ra-224) on the collector. Due to the short duration ofcollection it was impractical to accurately measure alpha particlespectrum of Th-228 on the collector (resulting from the decay of U-232on the source). The activity distribution of the source and thecollector surface was further measured using a Fuji imaging Plate™, fortime exposures of 10 minutes for the source and 57 minutes for thecollector.

FIGS. 3 a-b show the measurements of the Fuji Plate™, where FIG. 3 ashow the activity distribution of the collector, and FIG. 3 b show theactivity distribution of the source. As show, uniform activitydistributions were obtained both for the collector and the source.

The measured desorption probability for the most dilute solution tested(about 7.5 nanocuries per microliter) was about 35%. This result is tobe compared with the (theoretical) maximal desorption probability, atzero depth deposition, which is 50%. For high density solution (1microcurie per nicroliter) a desorption probability of about 25% wasobtained.

Example 3 An Experiment on Mice Having a LAPC4 Prostate Tumor

Following is a description of an experiment on two mice having humanLAPC4 prostate tumors. The objective of the experiment was to assess thetransport ranges of short-lived alpha-emitting atoms released by theradiotherapy device inside a living tumor.

Materials and Methods

The radiotherapy device used in all parts of the experiment was anickel-clad needle having Ra-224 atoms adsorbed on the surface of itstip. The preparation of the radiotherapy device was according to thedescription of Example 1, with exposure time of 69 hours to a 1.2microCurie source of Th-228, resulting in needle activity of about 50nanoCurie. In this experiment, the needle was not coated after theexposure.

The Ra-224 atoms on the needle disintegrated by alpha decay (half-lifeof 3.7 d) and release into the environment short-lived atoms: Rn-220(half-life of 56 s), Po-216 (half-life of 0.15 s) and Pb-212 (half-lifeof 10.6 h). The short-lived atoms dispersed in the immediate surroundingof the radiotherapy device by both convection via body fluids andthermal diffusion, and disintegrated by alpha decay. The size and theshape of the irradiated region depend on the specific trajectories ofthe short-lived atoms prior to their decay.

The radiation emitted from the radiotherapy device and its short-liveddecay products was measured using a Fuji imaging Plate™. Thephotostimulable phosphor of the imaging plate records both beta decayelectrons, whose range in the tissue is of the order of a fewmillimeters, and alpha-particles, whose range is a few dozen microns.The Ra-224 decay chain contains two beta-decays. Thus, when an imagingdetecting probe made of photostimulable phosphor, is inserted into thetumor, the effective detection volume for beta radiation issignificantly larger than the effective detection volume of alpharadiation.

Due to the short range of the alpha particles, detection thereofindicates the exact location of the decaying nuclei. Therefore, theprimary interest in this experiment was to separate reading of alpharadiation from background beta radiation. The separation was based onthe differences in the ranges of alpha- and beta-particles inside theactive part of the imaging material. More specifically, imprints made byalpha particles were typically in the form of localized hot-spotsspanning over 1-2 pixels (the area of each pixel is abut 200×200 μm²),whereas imprints made by beta decay electrons were “smeared” over manypixels and were of lower intensity. This distinction is particularlyrelevant to alpha particles arriving at the imaging material from itsimmediate surrounding, and is generally applicable when the totalradiation intensity is low.

The experiment included four in vivo measurements, in which a source anddetection detecting probes were inserted into the tumor for a fewminutes. In addition, the experiment included a prolonged stage, inwhich the source was kept inside the tumor of the living mouse for 3days. The analysis of the prolonged stage was made ex vivo.

In Vivo Measurements:

Four short-duration measurements were performed on the first mouse. Foreach measurement, a different imaging detecting probe was used.

FIGS. 4 a-d are schematic illustration of the detecting probes used inthis experiment, respectively referred to herein as detecting probe1—detecting probe 4. Specifically, detecting probe 1 had a triangularshape, about 3 millimeters in width, detecting probe 2 had a triangularshape, about 2 millimeters in width, detecting probe 3 had an arrow-likeelongated pentagonal shape, about 3 millimeters in width and detectingprobe 4 had a needle-like shape, about 0.7 millimeters in width.

Table 1, below summarizes the procedures employed by each detectingprobe.

TABLE 1 Probe Measurement No. Organ Time Insertion Procedure 1 tumor 10minutes Inserted prior to the insertion of the needle. The needle's axiswas approximately in the detecting probe's plane and at a right anglethereto. The tip of the detecting probe and the needle were in physicalcontact. 2 tumor 17 minutes Inserted 3 minutes after the retraction ofdetecting probe 1 without moving the needle, approximately in the planeformed by the needle and detecting probe 1, 180° relative to the needle.The tip of the detecting probe was 0.5-1 mm spaced apart from theneedle. 3 tumor  6 minutes Inserted immediately after the retraction ofthe needle (5 minutes after the retraction of detecting probe 2), at 90°to the needle. The insertion trajectory crossed the point at which theneedle's tip had been and continued 3-4 mm inwards. 4 testicle 20minutes The detecting probe was inserted prior to (healthy) the needle,about 2 mm into the testicle. The needle was inserted at 120° to thedetecting probe, such that the distance between the tip of the detectingprobe and the tip of the needle was about 2 mm.

In all cases the detecting probe was retracted backwards along its axis,rinsed in HBSS solution, dried out, attached to a thin stainless steelplate and placed in a light-sealed box. Subsequently, the detectingprobes were scanned by a stimulating beam of light, using a scanningdevice.

Ex Vivo Measurements:

A second mouse served for a single experiment. The needle used in theabove experiments on the first mouse, was inserted into the secondmouse's tumor, and was trimmed so that only its tip area remained in thetumor. The skin was sewed over the tip of the needle and the source waskept inside the living mouse for 3 days. The tumor was subsequentlyremoved and sliced into 7 slices.

FIG. 5 is a schematic illustration of the 7 slices, enumerated 1-7, ofthe removed tumor. Slices 1-4 were cut using the same scalpel. Theboundary between slices 5 and 6, the boundary between slices 6 and 7,and the back side of slice 7 were cut with a clean scalpel. Also shownin FIG. 5 is a blood-filled cavity, observed in the vicinity of theneedle when the tumor was dissected.

Table 2, below, summarize the dimensions and location of slices 1-7. Thenumerical values are approximated to ±10%.

TABLE 2 Thickness Slice Area [mm²] [mm] Distance from Needle 1 5 × 6 1mm 1-2 mm 2 4 × 5 1-2 mm    1-2 mm 3 3 × 2 1 mm 1 mm 4 3 × 3 1 mm 1 mm,facing slice 3 on the other side of the needle 5 15 × 10 3 mm 2-3 mm,behind slice 3 6 6 × 4 1 mm 5-6 mm, behind slice 5 7  8 × 14 3-4 mm   6-7 mm, behind slice 6

The slices were placed on the phosphoimaging plate in a manner such thatthe sides closer to the needle were faced upward. Each slice was coveredby a piece of the phosphoimaging plate. The phosphoimaging plate and theslices were kept in ice to maintain a temperature of about 0° C. Thescanning device was used for taking two measurements, 2 hours and 13hours from the covering of the slices. The bottom plate recorded theactivity of the slices for 23 hours.

Slices 1, 2, 3, 4 and 6 were dislocated by about 2-3 mm during the 2hour measurement. No dislocation occurred during the 13 hoursmeasurement.

Results In Vivo Measurements:

Reference is now to FIGS. 6 a-b showing an image (FIG. 6 a) recorded bydetecting probe 1 and a corresponding radiation graph (FIG. 6 b). Themeasured signal is shown in FIG. 6 b on a logarithmic scale, as afunction of the radial distance from detecting probe 1. As shown inFIGS. 6 a-b, due to the physical contact between detecting probe 1 andthe needle, an enhanced signal centered at the contact point wasobserved. Referring to FIG. 6 b, the maximal signal (about 0.5 mm fromthe contact point) is about three orders of magnitude larger than thesignal at the peripherals. The enhanced signal was surrounded by aradially decaying “halo,” about 3 mm in radius, which is a consequenceof the optics of the scanning device, and does not represent a realradiation pattern. In addition, to the radially decaying “halo,” anaxially decaying pattern was observed along detecting probe 1, about 5mm in length, beginning at the contact point, primarily resulting frombeta decay. Alpha particles imprints were inconclusive on the axiallydecaying pattern.

FIGS. 7 a-b show an image (FIG. 7 a) recorded by detecting probe 2 and acorresponding radiation graph (FIG. 7 b). Due to the lack of physicalcontact between detecting probe 2 and the needle, the maximal signal issignificantly smaller then the maximal signal in detecting probe 1(about 35 times smaller, see FIGS. 6 b and 7 b). The geometrical shapeof detecting probe 2 (see FIG. 4 b) resulted in appearance of themaximal signal at a distance of about 1.5 mm from the needle. Similarlyto detecting probe 1, the measured pattern falls off with the distance,up to about 4-5 mm from the needle.

FIGS. 8 a-b show an image (FIG. 8 a) recorded by detecting probe 3 and acorresponding radiation graph (FIG. 8 b). As stated, detecting probe 3was inserted immediately after the retraction of the needle. This wasdone so as not to record electrons emitted by the needle, thereby tofocus on radiation emitted by the Rn-220 atoms. As shown in FIG. 8 a,the path of detecting probe 3 crossed the insertion point of the needle(designated by an arrow in FIG. 8 a) and continued about 3-4 mm inward.Referring to FIG. 8 b, the radiation intensity was relatively weakhaving a number of isolated peaks corresponding to imprint of alphaparticles. A representative example of an imprint of a single alphaparticle is designated by the word “alpha” in FIG. 8 a. Similarly todetecting probes 1 and 2, the radiation intensity falls off with thedistance from the location of the needle, up to about 5 mm from. Thefarthest peak was observed 5.1 mm from the insertion point.

The radiation intensity recorded by detecting probe 4, used, as stated,in a healthy testicle, was too weak to be analyzed.

Ex Vivo Measurements:

FIG. 9 shows radiation patterns recorded of slices 1-7, and a cleanreference plate, designated “ref.” The strongest signal was recorded ofslice 4, where a dark spot, about 1-2 mm in diameter and a peripheralhalo, about 3-4 mm in diameter, were observed. A relatively strongsignal was recorded of slice 3, about 6-7 mm in diameter. A clear,although somewhat weaker, signal was recorded of slice 5, about 2-3 mmfrom the needle. A very weak, but statistically valid, signal wasrecorded of slice 6, about 5-6 mm from the needle. No signal wasrecorded of slice 7.

The bottom imaging plate recorded a weak signal on the back side ofslice 5, about 5-6 mm from the needle. This finding is less significantthan the weak signal found on slice 6, because it may be the result ofelectrons arriving from the bulk of slice 5.

Discussion

A rough measurement of the needle's activity showed a drop from about60,000 to about 20,000 counts per minute after its retraction from thetumor. Such a drop is explained by the removal of the Ra atoms of theneedle, which, as stated was not coated in this experiment. The residualactivity of the needle came primarily from Pb-212 atoms adsorbed on theneedle during its preparation, meaning that the Ra-224 population on theneedle dropped by a factor substantially larger than 3. As a result ofthe removal of Ra-224 from the needle, the majority of the Ra-224 atomsremained in the first mouse, and the radiation patterns recorded in thelong-duration ex vivo experiment on the second mouse were weaker.

In spite of the massive Ra-224 removal in the first mouse, the insertionof the same needle into the tumor of the second mouse resulted in a 2-3mm cavity around the insertion point. Such formation is consistent celldestruction by radiation, although simple “mechanical” damage caused bythe insertion itself is yet not excluded. The weak signal recorded ofslice 6 in the ex vivo experiment, indicates transport of alpha-emittingatoms to a range of about 5-6 mm from the needle. The imprints of alphaparticles recorded by detecting probe 3, about 5 mm from the needle, canalso be considered as evidence of such migration.

Example 4 An Experiment on Mice Having a B-16 Melanoma

Following is a description of an experiment on two mice belonging to theC57B1/6 inbred, treated with B-16 melanoma cells (approximately 100,000cells at 0.1 ml of HBSS buffer per mouse). The radiotherapy wasimplemented 16 days after inoculation of the tumors, at which point thetumors sized 19.5 mm, for a first mouse, and 17.2 mm for a second mouse.

Materials and Methods

Two nominally identical radioactive sources were prepared (one for eachmouse). Each source consisted of a 0.45 mm diameter nickel-platedstainless steel needle, recoil implanted in vacuum with Ra-224. Afterthe vacuum implantation, both needles were rinsed in deionized water andwashed in a stream of dry N₂, in order to minimize the release of Raatoms from the surface after insertion. The ²²⁴Ra activity uponinsertion was approximately 1-2 nanoCurie in each case.

The Ra-224 atoms on the needle disintegrated by alpha decay as furtherdetailed hereinabove (see, e.g., Example 3).

The needles were inserted subcutaneously to a depth of about 5 mm intoeach tumor, and were externally trimmed thereafter. The mice were keptalive for two days after insertion, at which point the tumors wereremoved and dissected manually at measured distances from the source(beginning at the periphery towards the insertion point and using adifferent scalpel for each dissection to avoid cross contamination). Aseries of samples, each about 1 mm³ in volume, were taken from thedissected parts, 5 from the first mouse, and 4 from the second mouse.Each sample was flattened between a glass microscope slide and a 7 μmMylar® foil, covering a surface of about 2-4 cm².

All samples were placed on a Fuji™ plate, using the Mylar® foil forphysical separation between the samples and the plate. Three consecutivemeasurements were taken. A first measurement started at t=0 for aduration of ΔT=5 hours, a second measurement started at t=6.75 hours fora duration of ΔT=17.1 hours and a third measurement started at t=25hours for a duration of ΔT=5 hours.

Results

A clear signal appeared in all three measurements in samples taken 2 mmand 11 mm from the source in the first mouse, and 0.5 mm, 6 mm and 15 mmfrom the source in the second mouse. The time dependence of the measuredintensity correlated with the half life of Ra-224 (3.66 d). Nodiscernible signal was detected on the other samples.

FIGS. 10 a-f exemplify images (FIGS. 10 a, 10 c and 10 e) andcorresponding radiation graphs (FIGS. 10 b, 10 d and 10 f, respectively)of the three consecutive measurements taken about 11 mm from the needleof the first mouse. FIGS. 10 a-b correspond to the first measurement,FIGS. 10 c-d correspond to the second measurement and FIGS. 10 e-fcorrespond to the third measurement. As shown in FIGS. 10 a-f, theintensity of the signals decreases with time.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

1. A method of manufacturing a radiotherapy device, the methodcomprising: (a) providing a probe having a surface; (b) positioning saidsurface in a flux of a radionuclide; and (c) collecting nuclei of saidradionuclide on or beneath said surface; wherein said steps (b) and (c)are done in a manner such that decay chain nuclei and alpha particles ofsaid radionuclide are emitted outside said surface; therebymanufacturing the radiotherapy device.
 2. The method of claim 1, whereinsaid collecting is by direct implantation in a vacuum.
 3. The method ofclaim 1, wherein said collecting is by connecting said surface to avoltage source of negative polarity.
 4. The method of claim 3, whereinsaid positioning of said surface in said flux of said radionuclide is ina gaseous environment.
 5. The method of claim 3, wherein a pressure ofsaid gaseous environment and a voltage of said voltage source areselected such that a velocity of nuclei is reduced to a thermalvelocity.
 6. The method of claim 1, wherein an outgoing flux of saiddecay chain nuclei is from about 10² to about 10⁵ atoms/sec.
 7. Themethod of claim 1, wherein said collection of said nuclei on or beneathsaid surface is done such that a surface density of said radionuclide isfrom about 10¹⁰ to about 10¹³ atoms/cm².
 8. The method of claim 1,wherein said probe comprises at least one needle.
 9. The method of claim1, wherein said probe comprises at least one bead.
 10. The method ofclaim 1, wherein said probe is a tip of an endoscope.
 11. The method ofclaim 1, wherein said probe is a tip of a laparoscope.
 12. The method ofclaim 1, wherein said probe is a tip of an imaging device.
 13. Themethod of claim 1, wherein said probe comprises an inner elongatedmember and an outer tubular member having a mouth section configured forreceiving said inner elongated member, said inner elongated member beingmovable within said outer tubular member and having a distal end and aproximal end, whereby said radionuclide is collected on or beneath asurface of said distal end.
 14. The method of claim 13, wherein saidouter tubular member comprises at least one window, for allowingprotrusion of said distal end of said inner elongated membertherethrough.
 15. The method of claim 13, wherein said at least onewindow is on a side wall of said outer tubular member.
 16. The method ofclaim 13, further comprising connecting an operating wire to saidproximal end of said inner elongated member.
 17. The method of claim 13,wherein said outer tubular member is made of a material capable of atleast partially absorbing said decay chain nuclei and said alphaparticles.
 18. The method of claim 13, wherein said inner elongatedmember and said outer tubular member are each independently flexible.19. The method of claim 1, further comprising coating said surface by aprotective coat.
 20. The method of claim 19, wherein at least one of athickness and a material of said protective coat is selected so as notto prevent emission of decay chain nuclei and alpha particles from saidsurface of said probe.
 21. The method of claim 1, wherein said probe iscapable of administering from about 100 rem to about 100000 rem ofradiation dose.
 22. The method of claim 1, wherein an activity of saidradionuclide is from about 10 nanoCurie to about 10 microCurie.